Dental Root Canal Filling Material Composition

This application is based on and claims priority to U.S. application Ser. No. 17/607,642 (filed on Oct. 29, 2021), which is the U.S. national stage application of International Application Serial No. PCT/JP2019/018754 (filed on May 10, 2019), the contents of which are hereby incorporated by reference in their entirety.

The present invention relates to a dental root canal filling material composition.

The root canal of a tooth has a dental pulp therein including nerves and blood vessels. When a dental pulp is infected or inflamed due to a deep dental caries, a fractured tooth crown, or the like and is allowed to go untreated, an abscess may be formed at the root apex of the root canal, the inflammation may spread in the periapical tissue, the gum may swell, or general symptoms such as swollen lymph nodes and fever may develop in some cases. Hence, when a dental pulp is infected or inflamed, the dental pulp is removed as needed, then the inside of the root canal is disinfected, and the dental pulp cavity is sealed with a root canal filling material to block stimuli to the periapical tissue.

Conventional root canal disinfectants contain active components such as formalin, paraformaldehyde, parachlorophenol, guaiacol, eugenol, zinc oxide, and calcium hydroxide.

Formalin and paraformaldehyde cause coagulation necrosis of protein, thus function to protect the internal tissue, and also have very strong bactericidal activity or disinfectant activity. Parachlorophenol, guaiacol, and eugenol have disinfectant activity and strong analgesic activity. Zinc oxide has disinfectant activity and anti-inflammatory activity. These components, however, have no activity to promote the healing of a root canal-periapical tissue.

In contrast, calcium hydroxide has disinfectant activity and analgesic activity and is believed to have an activity to promote healing of the root canal-periapical tissue. Hence, in Europe and America, calcium hydroxide has been commonly used as an active component in infected root canal therapeutic agents, and in Japan, dental treatment preparations containing calcium hydroxide have been developed and improved.

The application development of calcium hydroxide in the dental treatment preparations will be described in detail. Calcium hydroxide is a white powder, and an aqueous solution of calcium hydroxide has a pH of 12.6, which is strong alkaline, and thus has a strong disinfectant activity. Calcium hydroxide also has an activity to promote the formation of hard tissue of dental enamel, dentine, and dental cementum and thus has been contained in pulp capping materials, vital pulpotomy materials, root canal filling materials, and similar materials (Dental Outlook, 72(1), 63-74, 1988; The Journal of Japan Endodontic Association, 16(1), 47-51, 1995; and The Japanese Journal of Pediatric Dentistry, 26(3), 611-620, 1988).

Calcium hydroxide has also been widely used for apexification of a tooth with an immature root canal, sealing of a perforated site, and similar purposes (The Journal of Japan Endodontic Association, 14(2), 89-95, 1993; The Journal of Japan Endodontic Association, 16(1), 70-73, 1995; and The Japanese Journal of Pediatric Dentistry, 24(3), 459-467, 1986).

Calcium hydroxide is also used actively as a short-term disinfectant (temporary root canal filling material) during the treatment of an infected root canal (The Japanese Journal of Conservative Dentistry, 34 (3),986-992,1991; and International Endodontic Journal, 24, 119-125, 1991).

A root canal therapeutic agent containing calcium hydroxide is believed to give less irritation to tissue and to have bactericidal activity due to strong alkalinity, soft tissue dissolving activity, analgesic activity, healing promoting activity, exudate stop activity, dental root absorption inhibiting activity, hard tissue formation inducing activity, and the like. As described above, calcium hydroxide is not merely an antiseptic but is believed to be a medicinal agent improving the healing of a root canal-periapical tissue.

A root canal filling material containing calcium hydroxide, which has excellent bactericidal activity and an activity to promote the healing of a root canal-periapical tissue, is useful, but insufficiently provides the activity to promote the healing of intractable pulpitis or apical periodontitis, for example, due to bacterial infection that is difficult to remove or to healing prevention by bacteria invaded into the lesion around a root canal or lesion at a root apex. There is therefore a demand for a root canal filling material capable of promoting the healing of intractable pulpitis or apical periodontitis.

The present invention has an objective to provide a root canal filling material composition having higher healing promoting activity than conventional root canal filling material compositions.

The inventors of the present invention have repeated studies in order to solve the above problem and have found that a root canal filling material composition comprising a lithium salt promotes the differentiation from dental pulp stem cells to osteoblasts to activate or stimulate the bone metabolism in a periapical lesion and activates or stimulates immune response. The inventors of the present invention have further found that the root canal filling material composition consequently has an excellent activity to promote the healing of a root canal-periapical tissue and effectively promotes the healing of intractable pulpitis and apical periodontitis that cannot be healed by conventional root canal filling materials.

The present invention has been completed on the basis of the above findings and provides the following root canal filling material compositions.

Intractable pulpitis or apical periodontitis, for example, due to bacterial infection that is difficult to remove from the dental pulp or to healing prevention by bacteria invaded into the lesion around a root canal or at a root apex is difficult to heal even with a root canal filling material containing calcium hydroxide that is believed to have healing promoting activity.

In contrast, the root canal filling material composition of the present invention comprises a lithium salt, thus promotes or induces differentiation from dental pulp stem cells to osteoblasts, and increases white blood cells to stimulate immunity. On the basis of these activities, the root canal filling material composition of the present invention suppresses the inflammation of a lesion such as a pustule in a dental pulp or around a root apex even in intractable pulpitis or apical periodontitis, and effectively promotes healing.

When the root canal filling material composition of the present invention comprises calcium hydroxide in addition to the lithium salt, the composition has excellent bactericidal activity and anti-inflammatory activity derived from calcium hydroxide, and the activity of promoting the healing of a root canal-root apex periodontal tissue is markedly or synergistically improved.

The inventors of the present invention have found that when a root canal filling material composition comprising a lithium salt is filled in a root canal, the lithium salt is insufficiently eluted in some cases. In this case, a larger amount of the lithium salt is required to be contained, and this may increase the price or may limit the preparation.

In contrast, a root canal filling material composition comprising water and a polyhydric alcohol in addition to the lithium salt and calcium hydroxide easily elutes the lithium salt after being filled in a root canal, and the root canal filling material composition comprising a small amount of a lithium salt can provide the function of healing a root canal-periapical tissue.

When a root canal filling material composition comprising calcium hydroxide is stored, calcium hydroxide may precipitate and separate, and when used, the composition may mainly elute only the liquid components, or calcium hydroxide may solidify in a syringe, and the paste may be difficult to discharge. In contrast, the root canal filling material composition comprising a lithium salt, calcium hydroxide, water, and a polyhydric alcohol can suppress such solid-liquid separation during storage.

The inventors of the present invention have also found that when calcium hydroxide is added to a root canal filling material composition comprising a lithium salt, the paste after preparation may harden or dry, and such a preparation is difficult to catch on a lentulo or to smoothly discharge from a syringe container or the like and is difficult to apply. In contrast, when the root canal filling material composition of the present invention is a composition comprising a lithium salt, calcium hydroxide, water, and a polyhydric alcohol, and the water is contained 1 to 2 times the lithium salt in terms of weight ratio, the composition has an appropriate flow, and the paste does not harden and is unlikely to dry. Hence, the composition can be smoothly discharged from a syringe container or the like and has excellent operability. The composition is unlikely to dry, thus the container or package of the composition needs no special design, and the composition can be easily developed to a product.

As mentioned above, according to the studies by the inventors of the present invention, a root canal filling material composition comprising a lithium salt may insufficiently elute the lithium salt after the root canal filling material composition is filled in a root canal. When a two-paste type root canal filling material composition comprises a paste A containing a higher fatty acid and rosin and a paste B containing magnesium oxide and a vegetable oil in combination, and one or both of the paste A and the paste B contain a lithium salt, the lithium salt is easily eluted after a mixture of the paste A and the paste B is filled in a root canal, and the root canal filling material composition comprising a small amount of the lithium salt can provide an excellent promoting function of healing a root canal-periapical tissue.

When a root canal filling material composition comprises a paste A containing a higher fatty acid and rosin and a paste B containing magnesium oxide and a vegetable oil in combination, and one or both of the paste A and the paste B contain a lithium salt, the root canal filling material composition has an appropriate flow and thus has high operability. For example, the composition is easily filled in a root canal and is easily caught on an instrument such as a lentulo and a gutta-percha point. The excellent operability includes high stringing property.

If the setting time is excessively short, the paste sets during mixing, and the hardened paste is difficult to feed into a root canal. If the setting time is excessively long, contamination is caused in a root apex with an exudate or blood from the periphery and reduces the sealing performance of the root apex. The combination composition has an appropriate setting time.

The combination composition has satisfactory storage stability, and the solid-liquid separation during storage is suppressed.

When a root canal filling material composition comprises a paste A and a paste B in combination and hardens by mixing the paste A and the paste B, one or both of the paste A and the paste B comprise a glass powder, the glass powder contains calcium oxide and silicon dioxide in a total amount of 50 to 100% by weight relative to the total amount of the glass powder, the weight ratio of the calcium oxide to the silicon dioxide (calcium oxide:silicon dioxide) is 6:4 to 3:7 in the glass powder, and one or both of the paste A and the paste B comprise a lithium salt, the lithium salt is easily eluted after a mixture of the paste A and the paste B is filled in a root canal, and the root canal filling material composition comprising a small amount of a lithium salt can provide a promoting function of healing a root canal-root apex periodontal tissue.

The root canal filling material composition comprising a glass powder and a lithium salt has an appropriate flow and thus has high operability. For example, the composition is easily filled in a root canal and is easily caught on an instrument such as a lentulo and a gutta-percha point. The excellent operability includes high stringing property. The composition also has an appropriate setting time. The composition has satisfactory storage stability, and the solid-liquid separation during storage is suppressed.

The root canal filling material composition comprising a glass powder and a lithium salt forms, in the living body, a crystal phase belonging to a space group of P6/m, such as hydroxyapatite, or forms a bone-like crystal. Bones and teeth, which constitute a large part of the hard tissue in the living body, contains hydroxyapatite as a main component. The root canal filling material composition generates, from its surface, a bone-like crystal having the same structure as the main component of teeth, then fills a small void formed between the filler and a dentine, and can be integrated through the crystal with the dentine and bone tissue. In particular, the property has a beneficial effect on filling a tooth root canal that is difficult to seal, such as a tooth with no root apex, including a deciduous tooth and an immature permanent tooth, a tooth without formation of an apical seat in infected root canal treatment, and a tooth having a root apex that is not widely opened by apicoectomy. The composition accordingly provides the close contact with a dentine and bone tissue to result in a satisfactory sealing performance and induces a hard tissue even in a case in which complete sealing cannot be achieved clinically.

When in the root canal filling material composition comprising a glass powder and a lithium salt, the paste A comprises, as components giving a setting property, one or more components selected from eugenol, guaiacol, a higher fatty acid, polyacrylic acid, and phosphoric acid, and the paste B comprises, as components giving a setting property, one or more components selected from calcium oxide, magnesium oxide, strontium oxide, zinc oxide, calcium phosphate, and aluminosilicate glass, the flow, operability, setting time, storage stability, and formation inducibility of bone-like crystals are further improved.

The present invention will now be described in detail.

A root canal filling material composition of the present invention is the root canal filling material composition that comprises a lithium salt.

The root canal filling material is also called a sealer for root canal filling, an intracanal medicament, a cavity filler, or a perforation repair material, for example.

The lithium salt may be any of inorganic acid salts and organic acid salts. Examples of the inorganic acid salt include a hydrochloride, a carbonate, a sulfate, a phosphate, a hydrobromide, and a nitrate. Examples of the organic acid salt include a polycarboxylate such as an orotinate (also called “orotate” or “uracil 6-carboxylate”), a citrate, a fumarate, a maleate, a succinate, and a malonate, a lactate, a tartrate, an acetate, a butyrate, a palmitate, a stearate, a methanesulfonate, a toluenesulfonate, a tosylate, and a napadisilate.

Specifically, an inorganic acid salt is preferred, and a hydrochloride and a carbonate are more preferred.

Lithium salts may be used singly or in combination of two or more of them.

The concentration of the lithium salt can be, for example, 0.0001% by weight or more, 0.001% by weight or more, or 0.005% by weight or more and is preferably 0.01% by weight or more, more preferably 0.05% by weight or more, and even more preferably 0.1% by weight or more relative to the total amount of the composition. A composition containing the lithium salt at a concentration within the above range can sufficiently promote the healing of pulpitis or apical periodontitis. The concentration of the lithium salt is preferably 20% by weight or less, more preferably 15% by weight or less, even more preferably 12% by weight or less, still more preferably 10% by weight or less, and further preferably 6% by weight or less relative to the total amount of the composition. A composition containing the lithium salt at a concentration within the above range does not cause lithium poisoning such as anorexia and emesis.

When the root canal filling material composition of the present invention is filled in the lesion in a root canal or periapical tissue, the composition induces the differentiation from dental pulp stem cells to osteoblasts and increases white blood cells to activate immunity. The root canal filling material composition of the present invention therefore can be used as a composition for inducing the differentiation of osteoblasts (specifically, inducing the differentiation of osteoblasts in the lesion in a root canal and/or periapical tissue), a composition for increasing white blood cells (specifically, increasing white blood cells in the lesion in a root apex and/or periapical tissue), and a composition for immunostimulation (specifically, immunostimulation in the lesion in a root apex and/or periapical tissue.

The differentiation of osteoblasts with the root canal filling material composition of the present invention is induced by the promotion of Colla1 expression or the promotion of Runx2 expression, and thus the root canal filling material composition of the present invention can be used as a composition for promoting Colla1 expression (specifically, a composition for promoting Colla1 expression in the lesion in a root canal and/or periapical tissue) or as a composition for promoting Runx2 expression (specifically, a composition for promoting Runx2 expression in the lesion in a root canal and/or periapical tissue).

As described above, pulpitis and apical periodontitis involve bacterial infection. Hence, the present invention encompasses a method of treating an infected root canal and/or an infected periapical tissue, and the method comprises filling the root canal of a patient having an infected root canal and/or an infected periapical tissue, with a composition comprising a lithium salt in an amount sufficient to treat the infected root canal and/or the infected periapical tissue.

The present invention also encompasses an immunostimulation method in the lesion in a root canal and/or periapical tissue, and the method comprises filling a root canal of a patient having a lesion in the root canal and/or the periapical tissue, with a composition comprising a lithium salt in an amount sufficient for immunostimulation in the lesion in the root canal and/or the periapical tissue.

The present invention also encompasses a method of inducing differentiation from dental pulp stem cells to osteoblasts in the lesion in a root canal and/or periapical tissue, and the method comprises filling a root canal of a patient having a lesion in the root canal and/or the periapical tissue, with a composition containing a lithium salt in an amount sufficient to induce the differentiation from dental pulp stem cells to osteoblasts in the lesion in the root canal and/or the periapical tissue.

The dosage amount or the filling amount of the composition containing a lithium salt sufficient to treat an infected root canal and/or an infected periapical tissue depends on the type of tooth or the shape of a root canal, and about 0.01 to 0.03 mL of a composition containing a lithium salt at the above concentration can be used. The dosage amount or the filling amount of the composition containing a lithium salt sufficient for immunostimulation or for inducing the differentiation from dental pulp stem cells to osteoblasts, in a lesion in a root canal and/or periapical tissue is substantially the same as above.

The patient can be a non-human animal or a human and is particularly preferably a human.

The root canal filling material composition of the present invention preferably has an absolute daily lithium amount in immersion liquid of 0.02 μg or more, more preferably 0.05 μg or more, and even more preferably 0.1 μg or more, as determined in accordance with the method in “Lithium elution test from apical foramen” in EXAMPLES. The amount can be 1 μg or more. The amount is preferably 5 mg or less, more preferably 1 mg or less, and even more preferably 0.1 mg or less. The amount can be 10 μg or less.

In a first embodiment, the root canal filling material composition of the present invention can further comprise a calcium compound.

Examples of the calcium compound include calcium hydroxide, calcium carbonate, calcium sulfate, calcium chloride, calcium acetate, calcium oxide, tricalcium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, and calcium dihydrogen pyrophosphate. Specifically, calcium hydroxide and calcium carbonate are preferred, and calcium hydroxide is more preferred.

Calcium compounds may be used singly or in combination of two or more of them.

In the composition containing a calcium compound (particularly calcium hydroxide), the concentration of the calcium compound (particularly calcium hydroxide) is preferably 2% by weight or more, more preferably 5% by weight or more, even more preferably 10% by weight or more, and still more preferably 20% by weight or more relative to the total amount of the composition. When containing calcium hydroxide at a concentration within the above range, the composition sufficiently provides the pharmaceutical effect, particularly the pharmaceutical effect of calcium hydroxide. The concentration of the calcium compound (particularly calcium hydroxide) is preferably 70% by weight or less, more preferably 50% by weight or less, and even more preferably 40% by weight or less relative to the total amount of the composition. When containing the calcium compound at a concentration within the above range, the composition is moderately hard and can be easily discharged even from a syringe container.

The root canal filling material composition of the present invention in the first embodiment may further comprise water.